This letter is in reference to the inspection of your facility located at 65 Infanteria Avenue km. 13.0, Puerto Rico Industrial Park, Carolina, Puerto Rico 00985 from March 21 to April 22, 2005, by an investigator from the U.S. Food and Drug Administration, San Juan District Office. The inspection revealed that the human drugs Omnicef OP 250mg/5mL and 125mg/5mL, manufactured by your firm, are adulterated within the meaning of 21 U.S.C. 351 (a) (2) (B) (Section 501(a) (2) (B) of the Federal Food, Drug and Cosmetic Act (the Act)), as described below.

1. Failure to comply with Title 21 Code of Federal Regulations (CFR) Section 211.110(a) - The control procedures established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of the drug product are deficient. From 2002 to the present, your firm has been obtaining assay out-of specification results due to either low or high fill weight variations of the finished powder (Powder for Oral Suspension) products. Similar deficiencies were brought to your attention during our previous inspection of September 26, 2003. Your firm failed to implement the appropriate corrective action to prevent the deficiency from recurring.

Your manufacturing processes are required to be robust and reproducible to assure that drug products comply with their predetermined specifications in meeting the requirements of the Act. Your manufacturing and quality control procedures have failed to identify, during filling operations, lots that are out-of-specification (OOS) for low or high fill weight.

During the manufacturing process of Omnicef OP, the following lots reported out-of-specification results for assay, content uniformity, or low fill weight after meeting the in-process weight check specifications:

Four additional investigations for lots manufactured during [redacted] were on-going at the time of the inspection.

Further review of the evidence collected during the referenced inspection disclosed a lack of assurance of your established fill weight limit specifications. Your firm established that the net weight of the drug product correlates directly to the potency [redacted]. Moreover, the New Drug Application Supplement [redacted] submitted to FDA describes the [redacted] as a [redacted]. The following lots obtained either out-of-specification assay results during release testing from samples that met specifications during in-process fill weight check testing or out-of-specification results during in-process fill weight check re-testing (as a result of an investigation) from samples that met assay specification during release testing, as follows:

Omnicef 250mg15mL - 30mL Lot [redacted] (manufactured in [redacted]). During a re-test, an acceptable assay release result of [redacted] percent was obtained (specification is [redacted] percent to [redacted] percent label claim). The assay result was from a composite sample of [redacted] units that was OOS for the bottle fill weight. The results for the bottle fill weight were between grams to [redacted]. The specification for fill weight is [redacted] to [redacted].

Omnicef 250mg/5mL - 60mL Lot [redacted] (validation lot manufactured in [redacted]). An out-of-specification assay result of [redacted] percent was obtained (specification is [redacted] percent to [redacted] percent label claim) from a sample with a bottle fill weight of [redacted] grams (specification for fill weight limit is [redacted] to [redacted].

Omnicef 125mg/5mL - l00mL Lot [redacted] manufactured in [redacted]). An out-of specification assay result of [redacted] percent was obtained (specification is from [redacted] percent to [redacted] percent label claim) from a sample with a bottle fill weight of [redacted] (specification for fill weight limitit is [redacted] to [redacted].

2. Failure to comply with 21 CFR Part 211.110(b) -The in-process specifications for the characteristics of in-process materials are not consistent with drug product final specifications. The examination and testing of samples do not assure that the drug product and in-process material conforms to specifications.

Your manufacturing and quality control procedures have failed to identify assay and fill weight non-conformance results during normal production processes.

Omnicef 125mg/5mL - 100mL, Lot [redacted] {manufactured in [redacted] was identified as failing to meet weight specifications after initial testing had acceptable results. Initially the lot met specifications for release; however, during a second verification of the unit's weight as part of investigation [redacted] (lot [redacted]) percent of the lot was rejected because it did not meet the fill weight limit specification. Failure of the lot to meet the fill weight limit specification was not detected by the manufacturing and quality control systems during the routine production process of the lot.

Regarding Omnicef 125mg15mL - 30mL, Lot [redacted], (manufactured in [redacted] out-of specification results were detected after the lot was re-evaluated as part of an expanded investigation relating to other lots and after further testing of portions of the same lot. The lot met the assay release specification at the [redacted] percent sampling point. However, during a second verification of the [redacted] percent sampling point, as part of investigation [redacted] for the same lot at percent sampling point, percent of the lot was rejected due to assay out-of-specification results obtained for the [redacted] percent sampling point portion. Failure of the lot to meet the assay specification at the [redacted] percent sampling point was not detected by your manufacturing and quality control systems during the routine production process of the lot.

3 . Failure to comply with 21 CFR Part 211.165(a) - There is no assurance that each lot conforms to its final specifications. Ornnicef 125mg/5mL (30mL) lot [redacted] (manufactured in [redacted] originally met the assay release specification at the [redacted] percent sampling point. However, during a second verification of the [redacted] percent sampling point, as part of investigation [redacted] for the same lot at [redacted] percent sampling point, [redacted] percent of the lot was rejected due to assay out-of-specification results obtained during the re-testing for the percent sampling point portion. There is no assurance that units distributed have the appropriate quality standards.

4 . Failure to comply with 21 CFR Part 211.198 - The current inspection documented under-filled complaints received at CEPFI International during [redacted] and [redacted]. These complaints represent the possible failure of your product to meet specifications. Furthermore, your firm failed to conduct an assessment of eight Postmarketing Adverse Drug Experience (PADE) reports which stated lack of effectiveness and could possibly relate to incidents of the drug product failing to meet assay and/or fill weight specifications. According to your firm's policy, the lot number is a requirement in order to open an investigation. Because these PADE reports did not contain a lot number, these incidents were not investigated. Nonetheless, your firm's knowledge of the assay and fill weight problems should prompt you to further investigate these reports.

5. Failure to comply with 21 CFR Part 211.192 - Your firm failed to identify and correct the root cause of the OOS for assay and fill weight for the Omnicef OP products. Your inability to identify the root cause of the OOS results prevents you from implementing the appropriate corrective actions to assure the quality of each unit being distributed.

We acknowledge receipt of your letter dated May 6, 2005 responding to the Form FDA-483 issued on April 22, 2005. Our evaluation finds that your response does not fully address the assay-fill weight non-conformance problem. Furthermore, you did not provide any corrective measures to assure that all units are in compliance with CGMP.

For example, your response failed to address incidents in which non-conforming units were detected in lots that were previously tested and reported to be in-compliance with their release specifications. In addition, your response failed to address the issue of lots found out-of-specification for assay after initially being reported as complying with the manufacturing weight limit. Your response also failed to address the fill weight limit setting procedure issue. According to the investigator your current procedures take the average weight of a certain number of bottles to determine the fill weight limits used during the filling. This practice may not be appropriate given the variable weights of the bottles, which your fiem has determined as a possible cause of the high or low weight fill problem. In addition, your response does not mention reconsidering the fill weight limit specifications.

Furthermore, within your "Additional Enhancement in the Packaging Area" under the "Predictive/Preventive Control" you mentioned the equipment as a cause or possible cause for the assay-fill weight non-conforming excursions. However, during the inspection our Investigator found no documented evidence that any of the investigations for out of specifications assay results were related to equipment malfunction events. Therefore, although we recognize that corrective actions related to preventive maintenance of equipment is an improvement, at this point the equipment has not been directly related to the assay-fill weight problem, and other corrective actions would be appropriate.

We also acknowledge your decision to cease manufacturing Omnicef OP 125mg/5mL and 250mg15mL. 30mL (30cc) presentation, until the new equipment (filling line) is qualified. However, this corrective action fails to address similar deficiencies documented for the 60mL, and 100mL presentations of this product in either strength.

Federal agencies are advised of the issuance of all warning letters to drug manufactures so that they may take this information into account when considering the award of contracts. Additionally, pending NDA, ANDA, or export certificate requests may not be approved until the above violations are corrected.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizing your products or obtaining a court injunction.

Please notify this office in writing, within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, please state the reasons for the delay and the timeframe within which the corrections will be completed.

Your written reply to these concerns should be directed to the Food and Drug Administration, attention: Carlos A . Medina, Compliance Officer, at 466 Fernandez Juncos Avenue, San Juan, Puerto Rico 00901-3223. If you have any questions regarding any issue in this letter, please contact Mr. Medina at (787) 474-9538, cmedinal@ora.fda.gov. You can also find the Act, regulations and guidelines through links in FDA's Internet homepage at http://www.fda.gov.